To explore the effects of diabetes on myocardial function and metabolism we injected male rats with streptozotocin and studied their hearts 8 weeks later. Blood sugar levels in the treated rats were about 600 mg/100 ml. Body and heart growth rates were diminished. When studied in an isolated working rat heart apparatus using 5.5 mM glucose, hearts of diabetic animals showed diminished cardiac output and stroke work at high filling pressures. There also were significant depressions in peak left ventricular systolic pressure, peak aortic flow rate, maximum negative dP/dt, myocardial oxygen extraction, myocardial lactate production, and effluent lactate:pyruvate ratios. Myocardial glycogen stores, calculated glycogen utilization, and pyruvate production were increased in hearts of diabetics, and myocardial oxygen consumption was the same as in control hearts. The end-diastolic pressure-volume relationship was shifted to the right in hearts of diabetics. Most of the abnormalities observed in hearts of diabetic rats persisted when insulin and 15 mM glucose were included in the perfusion medium. Hearts from young rats or from age-matched food-restricted rats with heart weights similar to those of diabetics did not show depressed function or a pressure-volume shift. Our findings indicate that streptozotocin diabetes in rats results in abnormal myocardial performance. This is not due to restrictions in coronary flow or myocardial oxygenation and is not correctable by the provision of high glucose plus insulin in the perfusion medium.

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In order to determine whether diabetic cardiomyopathy in rats is associated with altered contractile proteins, male and female rats were made diabetic with intravenous streptozotocin (STZ). Calcium ATPase activity of cardiac actomyosin was significantly decreased after 1 week of diabetes and was depressed by 60% by 2 weeks. Rats pretreated with 3-O-methyl glucose to prevent the hyperglycemia caused by STZ had normal Ca2+-actomyosin ATPase activities, and non-diabetic rats whose food was restricted to keep their body and heart weights similar to those found in diabetic animals had only a slight fall in actomyosin ATPase activity. Ca2+-ATPase and actin-activated ATPase activities of pure myosin were similarly depressed in preparations from hearts of diabetic animals. Sodium dodecylsulfate gel electrophoresis and isoelectric focusing failed to reveal differences in the patterns of contractile proteins or light subunits between diabetics and controls, but pyrophosphate gels showed a shift in the myosin pattern. Because of depressed circulating thyroid hormone levels in diabetic animals, cardiac contractile proteins were also studied in preparations from thyroidectomized rats. Calcium activities of actomyosin and myosin ATPase were lower than values found in hearts of diabetic rats. When diabetic animals were kept euthyroid with thyroid replacement, actomyosin ATPase activity was still depressed. Thus STZ diabetes causes a significant decrease in cardiac contractile protein ATPase activity. This may be related to altered proportions of myosin isoenzymes.

A B S T R A C T The dynamic and metabolic performance of rats conditioned by a swimming program (CH) and hearts of sedentary rats (SH) was studied in an isolated working rat heart apparatus. Heart rate, filling pressure, and afterload were controlled or kept constant, and heart weights were comparable in both groups.When compared with SH, CH had increased cardiac output and cardiac work. Atrial pacing at more rapid rates caused greater differences in these functions, and left ventricular pressure and maximal rate of pressure rise (dp/dt) became higher in CH than in SH. Atrial pacing was associated in CH with increased oxygen consumption but in SH by increased lactate and pyruvate production.When atrial filling pressure was elevated in order to perform ventricular function curves, CH showed greater dynamic responses than SH. There were also greater increments in oxygen consumption, and the ratio of aerobic to anaerobic energy production was also higher in CH.The mechanism of increasing oxygen consumption during stress in CH was mainly by improved coronary flow. In SH coronary flow did not change, but extraction of oxygen from the perfusing fluid increased.The results indicate that in physically trained rats the function of the heart as a pump is improved. These hearts have greater aerobic and mechanical reserve than hearts of sedentary animals. These effects appear to be at least partially due to improved mechanisms of oxygen delivery.